Generally, all forms of shock (e.g., hemorrhagic, cardiogenic, septic), tissue injury (e.g., surgery, injury to battlefield combatants), local gastrointestinal inflammatory disease (e.g., inflammatory bowel disease), and/or ischemia lead to activation of inflammatory mediators, coagulation factors, and oxidative stress. In particular the activation of various humoral (e.g., complement factors, coagulation factors) and cellular elements (neutrophils, endothelial cells, macrophages) results in the expression of numerous mediators (toxic oxygen species, proteolytic enzymes, adherence molecules, cytokines), which can produce generalized inflammation and further tissue injury, ultimately leading to multiple organ failure. Furthermore, injury to organs such as in the gut can result in loss of barrier function and propagation/amplification of the inflammatory response.
In 2004, the Working Group on Trauma Research Program Summary Report (Hoyt D B, Holcomb J, Abraham E., Atkins J, Sopko G, Working Group on Trauma Research: Working Group on Trauma Research Program summary report: National Heart Lung Blood Institute (NHLBI), National Institute of General Medical Sciences (NIGMS), and National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), and the Department of Defense (DOD), J Trauma 2004; 57: 410-5) concluded that the “ability to manipulate the immune response following injury is essential to improving postinjury therapy.” However, systemic manipulation of the immune response can be risky given its inherent importance in fighting infection. Thus, a more targeted approach is likely to be potentially safer and more effective.
Potential targets include the plasma compartment and the gut lumen. There are at least four ways in which inflammatory mediators can be expressed in the gut lumen. First, inflammatory mediators can be produced systemically, absorbed by the liver and then delivered to the gut lumen via liver bile. Second, inflammatory mediators can be produced by the liver and then delivered to the gut lumen via liver bile. Third, gut epithelial cells can produce inflammatory mediators locally in the gut lumen. Finally, inflammatory mediators can be generated by bacteria in the gastrointestinal tract reacting with white blood cells.
The plasma compartment is an attractive target, since the local expression of inflammatory mediators in tissues can be protective whereas systemic release typically is not. Similarly, inflammatory toxins in the gut lumen injure cells and compromise barrier function without serving a beneficial host response. Whether produced by the liver or produced elsewhere and removed by the liver, inflammatory mediators, such as cytokines, are delivered to the small bowel via the bile where they can cause local injury and be readsorbed into the systemic circulation. Rats given lipopolysaccharide intravenously show improved survival when there was external drainage of bile resulting in some protection of the gastrointestinal tract.